Testosterone Dose Response

If you've so much as picked up a newspaper in the last couple of weeks, or even a Time, Newsweek, Sports Illustrated, People, or friggin' Weekly Reader, you've no doubt been force fed yet another article about the horrors of steroids. Yep, steroids are no doubt what the terrorists are planning on dropping into our drinking water, thus creating a horrible epidemic of exploding livers and diminutive testicles that drop out of our pants like tiny popcorn kernels left over from last night's viewing of "The Secret Ya-Ya Sisterhood."

Thankfully, there's some real world research going on about steroid hormones (not much, mind you, but some). Recently, researachers Shalender Bhasin, Linda Woodhouse, Richard Casaburi et al. (of Charles R. Drew University of Medicine and Science, Harbor-University of California Los Angeles Medical Center, Washington University School of Medicine) did a pretty tidy little study on our beloved Testosterone (in this case, the hormone, not the magazine).

The title of the study is, "Testosterone dose-response relationships in healthy young men." As you might guess, they didn't study any 300 lb ripped-to-the-bone bodybuilders claiming to be drug free (yeah right). Instead, they focused on "normal" men and their responses to graded doses of this macho hormone.

Subjects

The subjects in this study consisted of 61 healthy men between the ages of 18-35 years. All had prior weightlifting experience, normal Tstosterone levels, and hadn't used any anabolic agents in the preceding year. All received monthly injections of a long-acting GnRH agonist to suppress endogenous Testosterone production (now that's gotta hurt). Depending on which group they were randomized to, subjects received one of five different weekly doses of Testosterone enanthate for five months (note: there were no significant differences between groups for any variable at the start of the study).

Remember, these are the test subject's values at the time the study began.

Two weeks before their first intramuscular injection, subjects began following a standardized diet consisting of 36 kcal/kg body weight per day (16.4 kcals/lb) and 1.2 grams protein per kilogram body weight per day (0.55 grams/lb). To put these values in perspective, a 176-pound male would have to ingest 2880 kcals/day and 96 grams of protein/day. To make sure subjects didn't change their dietary habits during the study, they were asked to complete 3-day food records and 24-hr food recalls every four weeks.

Activity Control

Here's the only part of the study that surprised me, at least initially  subjects were asked NOT to perform any type of strength training or endurance exercise during the entire study. This was done to avoid the potentially confounding influence that intense physical activity might have on the dependent variables. The more I thought about it, teasing out the effects that exercise might have on responses to Testosterone would have required an additional five groups (of men that did strength train). And as anyone who's done a research study will tell you, getting a sample size of 61 men is hard enough, but 120 men for a 20-week study? Yet another clear example of how time and monetary constraints influence research design.

Outcome (dependent) Variables

To underscore the comprehensive nature of this study, take a look at this list of outcome variables:

 Fat-free mass (via underwater weighing and DEXA)

 Fat mass (via underwater weighing and DEXA)

 Thigh muscle volume (via MRI)

 Quadriceps muscle volume (via MRI)

 Total body water (via deuterium dilution)

 Leg press strength (via 1-rep max)

 Sexual function and desire (via daily logs)

 Spatial cognition (via checkerboard test)

 Mood (via Hamilton depression and Young manic scales)

 Blood counts and clinical chemistries (too many analytes to list)

 Prostate specific antigen (PSA)

 Total cholesterol and various subfractions

 Total and free Tstosterone

 Luteinizing hormone (LH)

 Sex hormone binding globulin (SHBH)

 Insulin-like growth factor 1 (IGF-1)

Statistical Gymnastics (oops, I mean analyses)

This is where some very good studies sometimes go sour incorrect analyses of the data (can anyone say repeated T-tests and type-II error?). Luckily, these researchers did their homework and used ANOVA to compare the changes from baseline among the five groups. They even examined all variables for their distribution characteristics and log-transformed those variables that didn't meet the assumptions of a normal distribution prior to analysis.

Results

Okay, here's what you've been waiting for. Let's start with hormone changes. Remember, weekly shots of GnRH assured that each subject's endogenous Testosterone production was at a minimum. Not surprisingly, 25 and 50 mg of Testosterone per week didn't "replace" what the GnRH had shut down. 125 mg/week seemed to keep total and free Testosterone at an even keel, while 300 mg and 600 mg/week doses led to roughly a doubling and quadrupling of Testosterone levels. LH was suppressed at all doses while SHBG increased only with the highest two doses.

Relative to changes in body composition, the lowest two doses of Testosterone led to a significant increase in fat mass (eeew!) while the middle dose (125 mg) once again led to no change. Fat-free mass (aka lean body mass) increased by 5.3 kg (11.7 lb) in the 300 mg group and 8.5 kg (18.7 lb) in the 600 mg group. The ratio of total body water to fat-free mass didn't change in any of the groups, indicating that the increases in fat-free mass were not a result of water retention.

On to muscle size and performance. Following suit, the lowest two doses had basically no effect on thigh or quadriceps muscle volume, leg press strength, or leg power. The 300 mg and 600 mg doses however led to significant increases in all of these parameters. Rather than confuse you with comma spices and annoyingly long sentences, here's what the data look like in table form (note: the % increases represent the change from baseline to week 20).

Dose
Thigh muscle volume
Quad muscle volume
Leg strength
Leg power

300 mg
+9.9%
+8.7%
+16.4%
+16.5%

600 mg
+15.7%
+14.4%
+17.7%
+22.6%

Sexual function, visual-spatial cognition, mood and PSA levels didn't change in any of the groups. None of the blood chemistry or organ toxicity values (e.g., creatinine, bilirubin, ALT, AST, etc.) were altered, with the exception of dose-dependent decreases in HDL-C that ranged from 10-20% (5-8 mg/dL), and a 9.9% increase in hemoglobin in the 600 mg group (the absolute value of 155.7 g/L was still within normal clinical limits, though).

Conclusions

Back in 1985, a researcher named GB Forbes speculated that there was a linear relationship between Tstosterone dose and lean mass accretion. For years, athletes and scientists have nonetheless disagreed about the effect of anabolic steroids on strength, muscle mass, and health status. The data from this thorough study support Forbes' assertion: weekly injections of Testosterone enanthate result in dose-dependent increases in muscle mass, muscle size, strength, and power. The downside is that HDL-C tends to take a nasty dip and at higher doses hemoglobin levels rise a smidgeon.

On a final note, the researchers were quick to point out that there were considerable differences in the response to Testosterone administration within each group. Why? The most likely explanation is that Testosterone might differentially affect some (or all) of the many factors that are thought to control muscle growth, including: nutritional status, physical activity level, glucocorticoid, thyroid, and growth hormone levels, polymorphisms of the androgen receptor, myostatin levels, etc.

So even though this research was super thorough, it, like most studies, left scientists with more questions than answers.

As I read over this study for the tenth time, one thing is for sure: the athletes were right. Testosterone does increase strength, power, and muscle size without negatively affecting the kidneys, liver or, prostate  you just have to take enough of it (i.e., at least 300 mg/week). Now that Testosterone has been shown to improve muscle mass in the elderly, in normal men, and in those with wasting disorders, I wonder how long it will take for its rogue social status to disappear? Judging how the media handled the recent "anabolic steroids in baseball" scandal, we may still be a few decades away...

Tim Ziegenfuss, Ph.D., CSCS is the Chief Scientific Officer for an industry-leading, pharmaceutically-licensed nutritional supplement company. Tim is also an Adjunct Professor of Nutrition at Kent State University and has monthly columns in Physical Magazine and Muscular Development. Previously, "Dr. Z" spent five years as a college professor, teaching (Anatomy/Physiology, Sports Nutrition, Exercise Physiology) and researching sports supplements (creatine, protein, pyruvate, androstenedione, androstenediol, ma huang, ribose). You can contact Tim with questions about training, nutrition, or supplement use at: tzphd@hotmail.com

Although testosterone (T) administration can increase insulin-like growth factor-I (IGF-I) when administered to hypogonadal men, no studies have examined whether this occurs in normal men. The present study was undertaken to determine if an increase in IGF-I may be part of the anabolic effect of androgens. We enrolled 11 normal men in a randomized, double-blinded cross-over study. Subjects were assigned to receive either T enanthate (TE) (300 mg im, each week) or nandrolone (ND) decanoate (300 mg im, each week) for 6 weeks. After a washout period subjects were administered the alternate treatment. Pre- and posttreatment serum was analyzed for IGF-I by RIA after acid-ethanol extraction. Results expressed as mean +/- SEM (Table 1). IGF-binding protein-3 was measured by RIA and was unchanged in the TE treatment and decreased significantly after ND treatment. Although GH levels were not significantly different after either TE or ND treatment, they tended to increase after TE treatment (1.23 +/- 0.28 ng/mL vs. 3.3 +/- 1.03 ng/mL) but remained unchanged after ND treatment (1.68 +/- 0.68 ng/mL vs. 1.89 +/- 0.64 ng/mL). Serum total T levels increased 32 +/- 0.05 nmol/L in the TE-treated men, but fell by 7 +/- 0.02 nmol/L in the ND-treated men (P &lt; 0.0001). Serum estradiol levels rose by 193.04 +/- 19.82 pmol/L in the TE-treated men although falling by 50.65 +/- 34.50 pmol/L in the ND-treated men (P &lt; 0.0002). These data indicate that when normal men are given TE, serum IGF-I levels increase after 6 weeks of treatment. Treatment with ND did not change serum levels of IGF-I but did decrease the level of the major serum IGF-BP and therefore the level of bioavailable IGF-I may be increased in the ND group.